Quinolinecarboxylic acid antibacterial agents

ABSTRACT

Novel 8-alkenyl, alkynyl, allenyl and cycloalkyl-quinolinecarboxylic acids are described as antibacterial agents as well as methods of manufacture including novel intermediates used in said manufacture.

This is a divisional of U.S. application Ser. No. 835,651 of Feb. 13,1992, now U.S. Pat. No. 5,175,356, which is a divisional of U.S.application Ser. No. 687,254 of Apr. 18, 1991, now U.S. Pat. No.5,116,834, which is a divisional of U.S. application Ser. No. 508,886 ofApr. 12, 1990, now U.S. Pat. No. 5,047,538.

BACKGROUND OF THE INVENTION

While 8-alkylquinolinecarboxylic acids have been described in theliterature as having antibacterial activity, the present 8-alkenyl,alkynyl, and cyclo-alkylquinolinecarboxylic acids provide novelantibacterial agents.

SUMMARY OF THE INVENTION

Accordindly, the present invention in a first aspeot is a compound ofFormula I ##STR1## wherein

X is alkenyl, alkynyl, allenyl, cycloalkyl, or alkylsubstitutedcycloalkyl;

Y is hydrogen, fluoro, or amino;

Z is a secondary cyclic amino group of the formulae ##STR2## wherein

n is 1,2,3, or 4;

n' is 1, 2, 3, or 4;

n +n' is a total of 2, 3, 4, or 5;

n" is 0, 1, or 2;

n'" is 0 or 1;

R₁ is hydrogen, an alkyl of from one to six carbon atoms or a cation;

R₂ is alkyl of from one to four carbon atoms, vinyl, haloalkyl, orhydroxyalkyl of from one to four carbon atoms, cycloalkyl of from threeto six carbon atoms, or phenyl or phenyl substituted by one or morehalogen atoms;

R₃ is hydrogen, alkyl of from one to four carbon atoms, or a cycloalkylof from three to six carbon atoms;

R₄ is hydrogen, alkyl of from one to four carbon atoms, hydroxyalkyl offrom two to four carbon atoms, trifluoroethyl, or R₄ CO wherein R₄ isalkyl of from one to four carbon atoms, or alkoxy of from one to fourcarbon atoms;

R₅ and R₆ are each independently hydrogen or alkyl of from one to threecarbon atoms;

R₇ is hydrogen, alkyl of from one to three carbon atoms, hydroxyalkyl offrom two to three carbon atoms, benzyl, or p-aminobenzyl;

R₈ and R₉ are each independently hydrogen, alkanoyl of from one to threecarbon atoms, alkyl of from one to three carbon atoms, isopropyl, orcyclopropyl;

R₁₀ and R₁₁ are each independently hydrogen, methyl, ethyl, or benzyl;

R₁₂, R₁₃, and R₁₄ are each independently hydrogen or methyl;

R₁₅ and R₁₆ are each independently hydrogen, halogen, NR₁₇ R₁₈, OR₁₇,SR₁₇, alkyl of from one to three carbon atoms, wherein R:: and R s areeach independently hydrogen, alkyl of from one to three carbon atoms, oralkanoyl of from one to three carbon atoms;

or a pharmaceutically acceptable acid addition or base salt thereof.

Another aspect of the invention is a process for preparing compounds ofFormula I ##STR3## wherein Y, Z, X, R₁, and R₂ are as defined above byreacting a compound of Formula IV (hereinafter shown), where Z¹ is ahalogen atom, with an appropriate secondary amine.

Certain novel intermediates in the process for preparing a compound ofFormula I are also included in the present invention. They include acompound of Formula II ##STR4## wherein X, Y, R₁, and R₂ are as definedabove and a compound of Formula III ##STR5## wherein X, Y, and R₁ are asdefined above.

The invention also includes a pharmaceutical composition which comprisesan antibacterially effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.

The invention further includes a method for treating bacterialinfections in mammals which comprises administering an antibacteriallyeffective amount of the above defined pharmaceutical composition to amammal in need thereof.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Substituents for the compounds of Formula I are defined hereafter.

The alkyl groups contemplated by the invention comprise both straightand branched carbon chains of from one to about six carbon atoms.Representative of such groups are methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tertiary-butyl, and the like.

The alkenyl groups contemplated by the invention comprise both straightand branched carbon chains of from two to ten carbon atoms.Representative of such groups are ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and the like.

The alkynyl groups contemplated by the invention comprise a carbon chainof from two to eight carbon atoms. Representative of such groups areethynyl, 1-propynyl, 2-propynyl, and the like.

The allenyl groups contemplated by the invention comprise a carbon chainof from three to ten carbon atoms containing two consecutive doublebonded carbon atoms. Representative of such groups are allene, and thelike.

The cycloalkyl groups contemplated by the invention comprise thosehaving three to six carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term alkanoyl is intended to include ##STR6## groups wherein R: isan alkyl of from one to three carbon atoms.

The hydroxyalkyl groups contemplated by the invention comprise thosehaving two to four carbon atoms such as 2-hydroxyethyl, 2- or3-hydroxypropyl, or 2-, 3-, or 4-hydroxybutyl.

The alkoxy groups contemplated by the invention comprise both straightand branched carbon chains of from one to about six carbon atoms.Representative of such groups are methoxy, ethoxy, propoxy, i-propoxy,t-butoxy, hexoxy, and the like.

The term, haloalkyl, is intended to include halogen substituted straightand branched carbon chains of from two to four carbon atoms. Thoseskilled in the art will recognize that the halogen substituent may notbe present on the α-carbon atom of the chain. Representative of suchgroups are β-fluoroethyl, β-chloroethyl, β,β-dichloroethyl,β-chloropropyl, β-chloro-2-propyl, and the like.

The term halogen is intended to include fluorine, chlorine, bromine, andiodine.

Certain compounds of the invention may exist in optically active forms.The pure R isomer, pure S isomer as well as mixtures thereof; includingthe racemic mixtures, are contemplated by the invention. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. All such isomers as well as mixtures thereof are intended to beincluded in the invention. Certain side chains may contain more than onechiral center. In these cases the diasteroisomers may be separated andutilized individually. All such mixtures and separated mixtures arecontemplated by the invention.

The compounds of the invention are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as alkali and alkaline earthmetals or organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Also included are heavymetal salts such as, for example, silver, zinc, cobalt, and cerium. Suchheavy metal salts are effective in the treatment of burns, especiallywhen applied to the affected surface of a burn victim either directly orin combination with a physiologically acceptable carrier such as a waterdispersible, hydrophilic carrier. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenedi-amine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, lactic, citric, oxalic, malonic,salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic,methanesulfonic, and the like. The salts are prepared by contacting thefree base form with a sufficient amount of the desired acid to produceeither a mono or di salt in the conventional manner. The free base formsmay be regenerated by treating the salt form with a base. For example,dilute solutions of aqueous base may be utilized. Dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonatesolutions are suitable for this purpose. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but the salts are otherwise equivalentto their respective free base forms for purposes of the invention. Useof excess base where R' is hydrogen gives the corresponding basic salt.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention.

The preferred compounds of this invention are those of Formula I whereinY is hydrogen or amino and R₂ is ethyl, vinyl, 2-fluoroethyl,difluoroethyl, cyclopropyl, phenyl, 2-fluorophenyl, 4-fluorophenyl, or2,4-difluorophenyl.

Also preferred compounds of this invention are those wherein Z is##STR7##

Other preferred compounds of this invention are those wherein R₁ ishydrogen or a pharmaceutically acceptable base salt such as a metal oran amine salt.

Other preferred compounds of this invention are those wherein n" is zeroor one, R₃, R₅, and R₆ are hydrogen, methyl, ethyl, or n-propyl, and R₄is hydrogen.

The most preferred compounds are those wherein Z is ##STR8## wherein R₁is hydrogen, R₂ is ethyl, vinyl, 2-fluoroethyl, cyclopropyl, or2,4-difluorophenyl, and R₃ is hydrogen, methyl, ethyl, 1-propyl,2-propyl, R₅, R₆ are hydrogen or methyl, or a pharmaceuticallyacceptable acid addition or base salt thereof.

Additionally, the most preferred compounds include those wherein R₂ iscyclopropyl, Z is ##STR9## in which n" is 0 and 1 and R₃ is hydrogen,methyl, ethyl, 1-propyl, 2-propyl, R₅ and R₆ are hydrogen or methyl, andR₁ is hydrogen or a pharmaceutically acceptable base salt thereof.

Of the most preferred compounds of Formula I mentioned above, valuableare those wherein X is alkenyl of from two to ten carbon atoms, alkynylof from two to eight carbon atoms or cycloalkyl of from three to sixcarbon atoms. More valuable are those compounds of Formula I wherein Xis alkenyl from two to four carbon atoms, alkynyl of from two to threecarbon atoms, cyclobutyl or cyclopropyl. Most valuable are thosecompounds of Formula I wherein X is ethenyl, ethynyl or cyclopropyl.

Particularly preferred compounds of the present invention are:

1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoacid;

1-cyclopropyl-8-ethenyl-7-[3(S)-ethylamino)-methyl-1-pyrrolidine]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic

7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-3-quinocarboxylic acid;

1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-7-[3-[methylamino)methyl]-1-pyrrolidinyl]-3-quinolinecarboxylic acid:

1cyclopropyl-8-ethenyl-7-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-3-quinolinecarboxylicacid;

7-(3-amino-1-piperidinyl)-1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolcarboxylic acid; PG,13

1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic

1-cyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-8-ethenyl-6-fluoro-1,4-dihydro-4-quinolinecarboxylicacid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclo-propyl-8-ethenyl-6-fluoro-1,4-dihydro-4-quinolinecarboxylicacid, all isomers;

7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluoro-phenyl)-8-ethenyl-6-fluoro-1,4-dihydro-4-oquinolinecarboxylic acid;

1-(2,4-difluorophenyl)-8-ethenyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-py4-oxo-3-quinolinecarboxylic acid;

1-(2,4-difluorophenyl)-8-ethenyl-7-[3-[(methyl-amino)methyl]-1-pyrrolidinyl]-4-oxo-3carboxylicacid;

7-(3-amino-1-piperidinyl)-1-(2,4-difluoro-phenyl)-8-ethenyl-6-fluoro-1,4-dihydro-4-oxquinolinecarboxylic acid;

1-(2,4-difluorophenyl)-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoacid;

1-(2,4-difluorophenyl)-8-ethenyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxcarboxylic acid;

7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-8-ethenyl-6-fluoro-1,43-quinolinecarboxylic acid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-8-ethenyl-6-fluoro-1,43-quinolinecarboxylic acid, all isomers;

7-(3-amino-1-pyrrolidinyl)-1,8-dicyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyl

1,8-dicyclopropyl-6-fluoro-1,4-dihydro-7-[3-[(methylaminomethyl]-1-pyrrolidinyl]-4-oxo-quinolinecarboxylicacid;

1,8-dicyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-carboxylicacid;

7-(3-amino-1-piperidinyl)-1,8-dicyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxyli

1,8-dicyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid;

1,8-dicylopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-quinolinecarboxyli

1,8-dicyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-6-fluoro-1,4-dihydro-4-oxo-3-acid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl].1,8-dicyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-carboxylicacid;

7-(3-amino-1-pyrrolidinyl)-8-cyclopropyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4quinolinecarboxylicacid;

8-cyclopropyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1dinyl]-4-oxo-3-quinolinecarboxylicacid;

8-cyclopropyl-1-(2,4-difluorophenyl)-7-[3-[ethyl-amino)methyl]-1-pyrrolidinyl]-6-fluoro-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-piperidinyl)-8-cyclopropyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4carboxylicacid;

8-cyclopropyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-qcarboxylic acid;

8-cyclopropyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4quinolinecarboxylicacid;

8-cyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2- oyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4- ooxo-3-quinolinecarboxylic acid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-8-cyclo-propyl-1-(2,4-difluorophenyl-6-fluoro-1,4-oxo-3-quinolinecarboxylic acid;

7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-(1-methylethenyl)-4-o3-quinolinecarboxylic acid;

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[(methyl-amino)methyl]-1-pyrrolidinyl]-8-(1oxo-3-quinolinecarboxylicacid;

1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrro-lidinyl]-6-fluoro-1,4-dihydro-8-(1-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-piperidinyl)-1-cyclopropyl-6-fluoro-C'1,4-dihydro-8-(1-methylethenyl)-4-oxo-3-quinoline-carboxylic acid;

1-cyclopropyl-6-fluoro-1,4-dihydro-8-(1-methyl-ethenyl)-4-oxo-7-(1-piperazinyl)-3-quiacid;

1-cyclopropyl-6-fluoro-1,4-dihydro-8-(1-methyl-ethenyl)-7-(3-methyl-1-piperazinyl)-4-carboxylicacid;

1-cyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-6-fluoro-1,4-dihydro-8-(1-meth3-quinolinecarboxylic acid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-8-(1-meth4-oxo-3-quinolinecarboxylic acid;

7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluoro-phenyl)-6-fluoro-1,4-dihydro-8-(1-methylet4-oxo-3-quinolinecarboxylic acid;

1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-8-(1-methyl-ethenyl)-4-oxo-3-quinolinecarboxylicacid;

1-(2,4-difluorophenyl)-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-(1-methyl-ethenyl)-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-piperidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-8-(1-methylethequinolinecarboxylic acid;

1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-8-(1-methylethenyl)-4-oxo-7-(1-piperazinyquinolinecarboxylic acid;

1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-8-(1-methylethenyl)-7-(3-methyl-1-piperaz3-quinolinecarboxylic acid;

7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-8ethenyl)-4-oxo-3-quinolinecarboxylicacid;

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-8ethenyl)-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinocarboxylic acid;

1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-7-[3-(methylamino)methyl]-1-pyrrolidinyl]-4-quinolinecarboxylicacid;

1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-r>pyrrolidinyl]-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-piperidinyl)-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolcarboxylic acid;

1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic

1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoline-carboxylicacid;

1-cyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-8-ethynyl-6-fluoro-1,4-dihydro-4-quinolinecarboxylicacid;

7[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethynyl-6-fluoro-1,4-dihydro-4carboxylicacid;

7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-dihydro-4-oxcarboxylic acid;

1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-dihydro-7-3-(methylamino)methyl]-1-pyrrolid4-oxo-3-quinolinecarboxylic acid;

1-(2,4-difluorophenyl)-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-8-ethynyl-6-fluoro-1,3-quinolinecarboxylic acid;

7-(3-amino-1-piperidinyl)-1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-dihydro-4-oxocarboxylic acid;

1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoacid;

1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxcarboxylic acid;

7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,43-quinolinecarboxylic acid; and

7-3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-8-ethynyl-6-fluoro-1,4-di3-quinolinecarboxylic acid.

The compound of the present invention and of Formula I may be preparedgenerally by reacting a compound of the Formula IV ##STR10## wherein X,Y, R₁, and R₂ are as defined above and Z¹ is a halogen atom, preferablyfluorine, with an appropriate secondary amine, ZH, wherein Z is asdefined above, and, if desired, converting by known methods theresulting free zwitterion or ester to a free acid or a pharmaceuticallyacceptable acid addition or base salt thereof.

Starting from a readily available starting material, the compounds ofFormula I may be prepared by

(a) reacting 3-hydroxy-2,4,5-trifluoro benzoic acid with triflicanhydride, followed by reaction with the appropriate tin reagent, forexample, under palladium catalysis to form for example,2,4,5-trifluoro-3-vinylbenzoic acid;

(b) reacting the above benzoic acid with an activating group, forexample, oxalyl chloride or carbonyl diimidazole, and an alkyl hydrogenmalonate derivative and a base forming as, for example,2,4,5-trifluoro-β-oxo-3-vinyl benzene propionate;

(c) reacting the above product with alkyl orthoformate and aceticanhydride and the resulting ethoxy methylene β-oxobenzene propionatewith a primary amine, R₂ NH₂ wherein R₂ is as defined above, forming as,for example, an alkyl α-(N-R₂amino-methylene)-2,4,5-trifluoro-β-oxo-3-vinyl benzene propionate;

(d) cyclizing the above compound by reacting it with a base in a solventforming , for example, an alkyl-1-R₂-6,7,-difluoro-1,4,-dihydro-4-oxo-8-vinyl-3-quinoline carboxylate; and

(e) reacting the above ester with a secondary amine, ZNH wherein Z is asdefined above, and deesterifying the carboxylate forming thecorresponding carboxylic acid of Formula I and converting, if desired,the resulting acid to a pharmaceutically acceptable acid addition basesalt thereof.

By way of illustration, the following secondary amines may be used instep (a) above to form a compound of Formula I which may be converted,if desired, to a pharmaceutically acceptable acid addition or base saltthereof. ##STR11##

The above secondary amines are either commercially available or can beprepared by known methods from commercially available startingmaterials.

Some of the above secondary amines have one or two chiral centers andcan be resolved into their respective optical isomers and/or separatedinto their respective diastereoisomers in the case of two chiral centersby known methods as described by Y. Kimura, et al, Abstracts of the 1989ICAAC meeting, Houston, Tex.

The bicyclic bridged secondary amines are either readily availabel ormay be readily prepared from known starting material by standardprocedures or by variations thereof. For example exo- and endo-3-amino-8-azabicyclo[3.2.1]octanes have the structural formula A and the acetylderivatives B, ##STR12## may be readily prepared from the known startingmaterial 8-(phenylmethyl-8-azabicylco[3.2.1]octan-3-one oxime, [J. R.Bagley and T. N. Riley, J. Het. Chem., 19, 485 (1982)] by the followingreaction sequence. ##STR13##

Certain compounds of the invention having formula Z wherein Z is##STR14## are made by a novel process described hereinafter according toScheme I below. ##STR15##

The novel bridged compounds of the present invention are prepared byesterifying a 2,6-diamino-heptanedioic acid (1), preferably with thionylchloride and methanol, to form the corresponding 2,6-diaminoheptanedioicacid dimethyl ester hydrochloride (2). The 2,6-diaminoheptanedioic acidmay be substituted at the 2,3, or 4-positions each independently by analkyl, preferably by a methyl group. The reaction proceeds at reflux andthen is stirred for from 10 to 20 hours or overnight at roomtemperature.

The esterified compound is then reacted with a trialkylamine and analcohol such as, for example, 1-pentanol to form the corresponding6,8-diazabicyclo-[3.2.2]nonane-7,9-dione (3). The triethylamine is thepreferred reactant. A dilute solution is used. It is heated under refluxfor as long as 4 days.

The dione formed is reacted with an alkali metal hydride, preferablysodium hydride, and an unsubstituted or substituted benzylhalide to formthe corresponding 6,8-bis(substituted or unsubstitutedbenzyl)-6,8-diazabicyclo[3.2.2]nonane-7,9-dione (4). The benzyl groupmay be substituted by an alkyl of from one to four, an alkoxy, or ahalogen group. The benzyl group methylene may be substituted by alkyl,preferably by a methyl group. Preferably bromo-methylbenzene or anα-methyl benzyl halide such as chlorine, bromine, or iodine is used.

Alternatively when it is desired to prepare the dione substituted by,for example, a methyl group, the dione is reacted with butyllithium andan alkyl halide to form the corresponding bridgehead alkyl-substituted6,8-bis(substituted phenyl)-6,8-diazabicyclo [3.2.2]-nonane-7,9-dione(7).

The above bis-benzylated dione-containing compound is then reduced tothe corresponding 6,8-bis(substituted or unsubstitutedbenzyl)-6,8-diazabicyclo[3.2.2]nonane (7 or 5) with lithium aluminumhydride in tetrahydrofuran, diglyme, ether, diethylether or dioxane.Preferably tetrahydrofuran is used. The reduced compound is subsequentlydebenzylated by catalytic hydrogenation. Preferably palladium on carbon,to form a desired 6,8-diaza-bicylclo[3.2.2]nonane, hydrochloride (6 or8). The reaction occurs in methanol and water in a ratio of about 2:1.

Compounds of Formula II wherein Z¹ is fluorine are novel and part of thepresent invention. They are prepared as previously described fromcompounds of Formula III ##STR16## wherein X, Y, and R₁ are as definedabove. For example, the appropriate carboxylic acid of Formula III isreacted with an activating agent such as carbonyl diimidazole in asolvent such as tetrahydrofuran, THF, at about 25° C. to 40° C. and thentreated with the magnesium salt of monoethyl malonate at about 25° C. to40° C. to provide the desired ethyl2,4,5-trifluoro-β-oxo-3-(substituted)benzene propionate. Variouschlorinating or brominating agents may be used in conjunction with thedianion of ethyl hydrogen malonate at about -78° C. to -40° C.

The above propionate is reacted with an alkyl orthoformate and aceticanhydride and subsequently with a primary alkylamino R₂ NH₂, forming anethyl (N-R² aminomethylene)-3-oxo-3-aryl propionate derivative (5b). Thereactants are preferably ethyl orthoformate and cyclopropylamine,ethylamine, or 2,4-difluoroaniline. The reaction proceeds for about 1 to6 hours at reflux.

The above seco quinolone product is reacted with a base in an organicsolvent to cyclize the compound forming alkyl N-R₂-6,7-difluoro-8-substituted-quinol-4-one-3-carboxylate. A preferred baseis an alkali hydride such as sodium hydride or tertiary amine such astriethylamine and solvents includes but are not limited to t-butanol,DMSO, tetrahydrofuran. The reaction occurs at temperatures from about 3120° C. to 100° C.

The resulting quinolone is reacted with a secondary amine, ZNH. Possiblereaction solvents include acetonitrile, DMSO or DMF. The reactionproceeds at between 0° C. and 100° C. for a about 2 to 18 hours.Secondary amines reacted with the compound may be protected asnecessary. Possible secondary amines include but are not limited to allthe secondary amines described above by Z.

The quinoline is then deesterified and, if desired, converted to apharmaceutically acceptable acid addition or base salt thereof. Usefulconditions for deesterifying are sodium hydroxide in alcohol or hydrogenchloride in acetic acid. The deesterification occurs at 25° C. to 40° C.in sodium hydroxide for 18 to 24 hours.

Compounds of Formula III are also novel and form part of the presentinvention. These compounds may be prepared by a variety of methods fromreadily available starting materials.

One route involves converting tetrafluorophthalic acid to itscorresponding dimethyl ester by standard methods; treating said esterwith methanol and base, e.g., potassium carbonate, in dimethylsulfoxide,DMSO, to afford the dimethyl 3,4,6-trifluoro-5-methyoxyl-phthalate;treating said phthalate with aqueous acid, e.g., sulfuric acid, toprovide the 3-hydroxy-2,4,5-trifluorobenzoic acid. This key benzoic acidmay be used to prepare the compounds of Formula III.

For example, esterification of the acid and treatment of the hydroxygroup with trifluoromethane sulfonyl anhydride provides the3-trifluoromethyl sulfonyl-2,4,5-trifluoro methyl benzoate. Typicalchlorinating agents are oxalyl chloride or thionyl chloride. Thereactions are run in inert solvents such as methylene chloride ortoluene. Reaction of the ester with trifluoromethanesulfonyl anhydridein pyridine at about 25° C. to 30° C. for about 10 to 18 hours providesthe triflate derivative.

The triflate ester is treated with tri-n-butyl vinyltin under palladiumcatalysis, followed by reaction with a typical base (NaOH) provides2,4,5-trifluoro-3-vinyl benzoic acid. Typical palladium catalysis arePd(PPh₃)₄, Pd(Cl)₂ (OA₂)₂. The reactions are run in dioxane, DMF or THFat 40° C. to 120° C. for 10 to 24 hours.

Alternate routes to compounds of Formula III begin with1-bromo-2,4,5-trifluorobenzene. For example, lithiation of1-bromo-2,4,5-trifluorobenzene and treatment of the anion withN-formylpiperidine provides 5-bromo-2,3,6-trifluoro benzaldehyde.Typical procedures involve the use of a base, e.g., LDA (lithiumdiisopropylamide), in THF at about -78° C. to -100° C.

The 5-bromo-2,3,6-trifluorobenzaldehyde may be converted to compounds ofFormula III wherein X is alkenyl by treating said aldehyde with theappropriate alkyl triphenyl phosphonium iodide.

Compounds of Formula III where X is alkynyl may be prepared directlyfrom 1-bromo-2,4,5-trifluoro-benzene by treating said benzene first inbase, e.g., lithium diisopropylamide, at about -78° C. followed withiodine, treating the resulting 1-iodo-2,3,6-trifluoro-5-bromobenzenewith trimethylsilylacetylene in the presence of PdCl₂ and cuprous iodidein triethylamine at about 25° C., and converting the 1-bromo position tocarboxylic acid with, for example, n-butyl lithium and carbon dioxide,then removing the trimethylsilyl group by potassium carbonate inmethanol.

The compounds of the invention display anti-bacterial activity whentested by the microtitration dilution method as described in Heifetz, etal, Antimicr. Agents & Chemoth., 6, 124 (1974), which is incorporatedherein by reference.

By use of the above reference method, the following minimum inhibitoryconcentration value (MICs in μg/mL) shown in Table I were obtained forrepresentative compounds of the invention.

                  TABLE I    ______________________________________    In Vitro Antibacterial Activity    Minimal Inhibitory Concentration    MIC (μg/ml)    Organism           Ex. 1    Ex. 2  Ex. 3    ______________________________________    Enterobacter cloacae MA 2646                       0.1      0.1    0.2    Escherichia coli Vogel                       0.1      0.1    0.1    Escherichia coli H56                       0.05     0.05   0.1    Klebsiella pneumoniae MGH-2                       0.2      0.2    0.4    Proteus rettgeri M 1771                       0.4      0.4    0.4    Pseudomonas aeroginosa UI-18                       1.6      1.6    3.1    Staphylococcus aureus H228                       0.2      0.4    0.006    Staphylococcus aureus UC-76                       0.1      0.1    0.003    Streptococcus faecalis MGH-2                       0.4      0.4    0.013    Streptococcus pneumoniae SV-1                       0.2      0.4    0.003    Streptococcus pyogenes C-203                       0.2      0.4    0.013    ______________________________________

The compounds of the invention can be prepared and administered in awide variety of oral, parenteral and topical dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt of a compound of FormulaI.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, suppositories, andointments. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, or tablet disintegrating agents; it can also be anencapsulating material. In powders, the carrier is a finely dividedsolid which is in admixture with the finely divided active compound. Inthe tablet the active compound is mixed with carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 or 10 to about 70 percent of the active ingredient. Suitablesolid carriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and thelike. The term "preparation" is intended to include the formulation ofthe active compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Such solutions are prepared so as to beacceptable to biological systems (isotonicity, pH, etc). Liquidpreparations can also be formulated in solution in aqueous polyethyleneglycol solution. Aqueous solutions suitable for oral use can be preparedby dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents as desired.Aqueous suspension suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, i.e.,natural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other well-known suspending agents.

Ointment preparations contain heavy metal salts of a compound of FormulaI with physiologically acceptable carrier. The carrier is desirably aconventional water-dispersible hydrophilic or oil-in-water carrier,particularly a conventional semi-soft or cream-like water-dispersible orwater soluble, oil-in-water emulsion which may be applied to an affectedburn surface or infected surface with a minimum of discomfort. Suitablecompositions may be prepared by merely incorporating or homogeneouslyadmixing finely divided compounds with the hydrophilic carrier or baseor ointment.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, powders in vialsor ampules, and ointments in tubes or jars. The unit dosage form canalso be a capsule, cachet, tablet, gel or cream itself or it can be theappropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from I mg to 100 mg according to the particularapplication and the potency of the active ingredient.

In therapeutic use as agents for treating bacterial infections thecompounds utilized in the pharmaceutical method of this invention areadministered at the initial dosage of about 3 mg to about 40 mg perkilogram daily. A daily dose range of about 6 mg to about 14 mg perkilogram is preferred. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is with the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate methods for preparing thecompounds of the invention.

PREPARATION OF STARTING MATERIALS EXAMPLE A3-Hydroxy-2,4,5-trifluorobenzoic acid methyl ester

A solution of 3-hydroxy-2,4,5-trifluorobenzoic acid (50 g, 0.26 mol)(prepared in an analogous manner to that described in Eur. Pat.Publication 271275) in methylene chloride (500 mL) was added oxalylchloride (79 g, 0.62 mol). This solution was stirred at room temperaturefor 18 hours, cooled to 5° C. and then treated dropwise with methanol(100 mL). The mixture was stirred at room temperature for 2 hours,refluxed for 0.5 hour, cooled and concentrated. The residue waspartitioned between methylene chloride and saturated sodium bicarbonate.The organic layer was dried (MgSO₄) and concentrated to provide 16.7 gof the desired 3-hydroxy-2,4,5-trifluorobenzoic acid methyl ester.Acidification of the bicarbonate layer, extraction with ether andconcentration provided an additional 37 g of desired product asindicated by NMR, This material was not purified further but carriedinto the next step.

EXAMPLE B 2,4,5-Trifluoro-3-trifluoromethylsulfonyl benzoic acid, methylester

To a cooled solution (0° to 5° C.) of 3-hydroxy-2,4,5-trifluorobenzoicacid methyl ester (53.7 g, 0.26 mol) in methylene chloride (200 mL) andpyridine (21 g) was added a solution of trifluoromethane sulfonylanhydride (73 g, 0.26 mol) in methylene chloride (100 mL) dropwise. Thereaction was stirred at room temperature for 18 hours at which time anadditional 20 g of trifluoromethane sulfonyl anhydride was added.Stirring was continued for 5 additional hours. The reaction was dilutedwith 10% HCl (500 mL), the organic layer was dried and concentrated. Theresulting oil was distilled to provide 77.1 g (88%) of the desiredproduct; bp 80° C. to 100° C. (0.3 mm).

EXAMPLE C 3-Ethenyl-2,4,5-trifluorobenzoic acid

To a solution of 2,4,5-trifluoro-3-trifluoro methanesulfonyl benzoicacid, methyl ester (22.0 g, 0.065 mol) in dioxane (100 mL) was addedtri-n-butyl vinyl tin (21.6 g, 0.068 mol), lithium chloride (16.7 g,0.37 mL) 2,6-di-t-butyl-4-methylphenol (0.08 g) andpalladium-tetra-triphenyl phosphine (1.1 g). The mixture was heated at98° C. for 12 hours, cooled, diluted with ether and filtered throughcelite. The ether layer was concentrated and the resulting residuesuspended in hexane and filtered. The filtrate was concentrated to ayellow oil which was immediately dissolved in methanol (250 mL) and 1Nsodium hydroxide (150 mL . The mixture was stirred at room temperaturefor 4 hours, diluted with water and ether. The aqueous layer wasacidified (pH 2) with 6N HCl and extracted with methylene chloride. Theorganic layer was dried and concentrated to provide the desired product(9.6 g, 77%); mp 108°-110° C.

EXAMPLE D 3-Ethenyl-2,4,5-trifluoro-β-oxo-benzenepropanoic acid, ethylester

To a cooled solution (0° to 5° C.) of 3-ethenyl-2,4,5-trifluorobenzoicacid (6.0 g, 0.03 mol) (100 mL) was added carbonyl diimidazole (4.9 g,0.030 mol). The mixture was then stirred at room temperature for 1 hour,heated with magnesium bis-(ethyl malonate) (8.7 g, 0.03 mol) andrefluxed for 3 hours. The reaction was allowed to cool, treated with 3NHCl (30 mL) and stirred for 1.5 hours at room temperature. The reactionwas partitioned between ether and water. The organic layer was dried andconcentrated to provide 7.65 g (93%) of the desired product. Ananalytical sample was obtained by preparative TLC (SiOz, 9:1hexane/EtOAC) Analysis Calcd: C 57.36, H 4.17, F 20.94;

Found: C 57.39, H 4.16, F 21.22.

EXAMPLE E1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

3-Ethenyl-2,4,5-trifluoro-β-oxo-benzene propionic acid, ethyl ester (7.1g, 0.026 mol), ethyl ortho-formate (7 mL) and acetic anhydride (4 mL)were refluxed for 6 hours. The volatiles were removed under reducedpressure, and the residual oil was dissolved in THF (50 mL) and treateddropwise with cyclopropylamine (7.98 g, 0.034 mol) in 10 mL of THF at 0°C. The reaction was allowed to warm to room temperature and stirred for3 hours. The mixture was concentrated, dissolved in ether, filtered, andconcentrated to provide 7.6 g (86%) of an oil.

A solution ofα-cyclopropylaminomethylene-3-ethenyl-2,4,5-trifluoro-β-oxopropanoicacid, ethyl ester (7.3 g, 0.021 mol) in THF (100 mL) was added dropwiseto a cooled solution of NaH (1.1 g, 0.027 mol, 60% oil dispersion washedwith hexanes). The reaction was stirred for 1 hour at 0° C to 5° C., 0.5hour at room temperature and then quenched with acetic acid (1 mL). Theresulting solution was concentrated and the residue dissolved inchloroform, washed with HzO, dried and concentrated. The residue wassuspended in methanol (100 mL), treated with 1N sodium hydroxide at 0°C. and then stirred at room temperature for 2 hours. Acidification withlN HCl (110 mL) and filtration gave 3.9 g of the desired product. Ananalytical sample was obtained by recrystallization from ethyl acetate;mp 183°-188° C.

EXAMPLE F8-Ethenyl-6,7-difluoro-1-[1-(2,4-difluorobenzene)]-1,4-dihydro-4-oxo-3-quinolinecarboxy

This compound was prepared in a manner analogous to Example E.2,4-Difluoro aniline was used in place of cyclopropylamine to providethe ethyl ester. Treatment with sodium hydroxide provided 0.71 g (20%,from 3-ethenyl-α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropionic acid, ethyl ester); mp 217°-219° C.

EXAMPLE G 3-Cyclopropyl-2,4,5-trifluorobenzoic acid

A mixture of 3-ethenyl-2,4,5-trifluoro benzoic acid, ethyl ester (0.5 g,2.3 mmol), (N⁵ -cyclopenta-dienyl)dicarbonyl[(dimethylsulfonio)-methyl]iron tetrafluoroborate [J. Org.Chem., 54, 2467, (1989)](1.8 g, 4.6 mmol), and nitromethane (3 mL) washeated at refluxed for 20 hours. The resulting dark mixture was dilutedwith methylene chloride, filtered and concentrated to an oil. The oilwas dissolved in hexane, filtered and concentrated to provide 0.33 g ofthe ester. This material was dissolved in methanol (5 mL) and lN sodiumhydroxide (1.8 mL). After stirring for 1 hour, the mixture waspartitioned between HzO and ether, the aqueous layer was heated withcharcoal, filtered and acidified with lN HCl. The precipitate wasfiltered and dried to provide 0.17 g (38%) of the desired product; mp95°-97° C.

EXAMPLE H 3-Bromo-2,5,6-trifluorobenzaldehyde

To a solution of 1-bromo-2,4,5-trifluoro benzene (25 g, 0.12 mol) in THF(200 mL) at -78° C. was added LDA (80 mL, 1.5 M) dropwise. The mixturewas stirred at -78° C. for 1 hour, then N-formylpiperidine (16 g, 0.144mol) was added in one portion and stirring continued for 2 hours. Anadditional 15 g of N-for ylpiperidine was then added every 0.5 hour in 5g portions. The reaction was quenched with 3N HCl (pH 3) at -78° C. Thereaction was warmed to 0° C. and partitioned between zO and ether. Theether layer was dried and concentrated and the residue was distilled toprovide 13 g (45%) of the desired aldehyde; bp 63°-65° C. (0.2 mm).

EXAMPLE 11-Cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoacid

A mixture of1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (0.80 g, 2.9 mmol), 2-methylpiperazine (1.9 g, 19 mmol) andacetonitrile (5 mL) was heated at reflux for 22 hours. The mixture wascooled and concentrated. The residue was dissolved in HzO (50 mL),treated with charcoal and filtered through celite. The pH of thefiltrate was adjusted to 7, with HCl (3N) and after cooling to 0° C. theprecipitate was collected and dried to provide 0.81 g (78%) of thedesired product; mp 227°-231° dec.

EXAMPLE 21-Cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic

A mixture of1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (0.40 1.44 mmol), piperazine (0.80 g, 7.8 mmol), and CHaCN (3 mL)was refluxed for 16 hours. Workup was identical to that described inExample 1 to provide 0.28 g (54%) of the desired product; mp 213°-218°dec.

EXAMPLE 31-Cyclopropyl-8-ethenyl-7-3(S)-(ethylamino)methyl-1-pyrrolidine]-6-fluoro-1,4-dihydro-4-ocarboxylic acid

This compound was prepared in a manner analogous to that described inExample 1, a yield of 0.32 g (63%) was obtained; mp 206°-208° C. The3(S)-(ethyl-amino)methyl-1-pyrrolidine was obtained as described in J.Med. Chem., 30, 1711 (1987).

We claim:
 1. A compound of the formula ##STR17## wherein X is alkenylfrom two to ten carbon atoms, alkynyl from two to eight carbon atoms,cycloalkyl from three to six carbon atoms or cycloalkyl substituted byalkyl in which alkyl is one to four carbon atoms;Y is hydrogen, fluoroor amino; R₁ is hydrogen, alkyl of from one to six carbon atoms or acation; R₂ is alkyl of from one to four carbon atoms, vinyl, haloalkylor hydroxyalkyl of from one to four carbon atoms, cycloalkyl of fromthree to six carbon atoms, phenyl or phenyl substituted by one or morehalogen atoms; Z is a secondary cyclic amino group of the formulae;##STR18## wherein n'" is 0 or 1;R₃ is hydrogen, alkyl of from one tofour carbon atoms or a cycloalkyl of from three to six carbon atoms; R₅and R₆ are each independently hydrogen or alkyl of from one to threecarbon atoms; R₇ is hydrogen, alkyl of from one to three carbon atoms,hydroxyalkyl of from two to three carbon atoms, benzyl, orp-aminobenzyl; R₁₀ and R₁₁ are each independently hydrogen, methyl,ethyl, or benzyl; R₁₂, R₁₃, and R₁₄ are each independently hydrogen ormethyl; or a pharmaceutically acceptable acid addition salt thereof. 2.A compound according to claim 1 wherein Y is hydrogen or amino, and R₂is ethyl, vinyl, 2-fluoroethyl, difluoroethyl, cyclopropyl, phenyl,2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl.
 3. A compoundaccording to claim 2 wherein Z is ##STR19## wherein R₃ is hydrogen,methyl, ethyl, n-propyl, or 2-propyl, and R₅ and R₆ are hydrogen,methyl, or ethyl.
 4. A compound according to claim 3 wherein R₁ ishydrogen or a cation.
 5. A compound according to claim 4, where R₃ ishydrogen, methyl, ethyl or n-propyl and R₅ and R₆ are hydrogen, methylor ethyl.
 6. A compound according to claim 5, wherein Z is ##STR20##wherein R₁ is hydrogen; R₂ is ethyl, vinyl, 2-fluoroethyl, cyclopropylor 2,4-difluorophenyl; R₃ is hydrogen, methyl, ethyl n-propyl, and R₅and R₆ are hydrogen or methyl.
 7. A compound according to claim 6,wherein X is alkenyl of two to ten carbon atoms, alkynyl of two to eightcarbon atoms or cycloalkyl of three to six carbon atoms.
 8. A compoundaccording to claim 7, wherein X is alkenyl of two to four carbon atoms,alkynyl of two or three carbon atoms, cyclobutyl or cyclopropyl.
 9. Acompound according to claim 8, wherein X is ethenyl, ethynyl orcyclopropyl.
 10. A compound according to claim 9 and being1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid.
 11. A compoundaccording to claim 9 and being1-cyclopropyl-8-ethenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
 12. A pharmaceuticalcomposition comprising an antibacterially effective amount of a compoundas claimed in claim 1 together with a pharmaceutically acceptablecarrier.
 13. A method of treating bacterial infections in mammals whichcomprises administering to said mammal a pharmaceutical composition asclaimed in claim 12 in unit dosage form.